1. Field of the Invention
The present invention relates to liquid antacid compositions and methods for their preparation. More particularly, the present invention relates to preservative-free calcium carbonate liquid antacid compositions containing an additional alkaline compound as a pH adjusting agent. The compositions have a final product pH of greater than 9.0 providing for an enhanced resistance to microbial contamination and a better tasting product.
2. Description of the Related Art
Gastric antacids are agents that neutralize or remove acid from the gastric contents. Antacids are widely used in the treatment of various gastrointestinal disorders such as peptic ulcers and gastritis. Antacids are also used for the relief of acid indigestion, heartburn, dyspepsia, sour stomach, reflux esophagitis and the like. The clinical use of antacids is based on their ability to neutralize stomach acid and increase the pH of gastric secretions. Although antacids do not neutralize all gastric acid, increasing gastric pH from 1.3 to 2.3 neutralizes 90% and increasing pH to 3.3 neutralizes 99% of gastric acid. For optimal healing of peptic ulcers, most clinicians believe that gastric pH should be maintained at about 3-3.5. Accordingly, it is desirable that an antacid feature a high acid neutralization capacity and a rapid rate of gastric acid neutralization.
Antacids used today are made from a variety of inorganic salts such as calcium carbonate, sodium bicarbonate, magnesium salts and aluminum salts. Magnesium hydroxide and aluminum hydroxide are the most potent magnesium and aluminum compounds and are often used in combination. In addition, magnesium oxide, magnesium carbonate, aluminum phosphate, magaldrate and magnesium trisilicate are also employed.
Antacids are available in both liquid suspensions as well as solid dosage forms. In general, liquid antacid suspensions are preferred to tablets or powders since they are more rapidly and effectively solubilized and have a greater ability to react with and neutralize gastric acid.
One of the major concerns with antacid liquids is the lack of patient compliance due to the poor taste properties of liquid preparations. In addition to the inherent taste of the antacid actives there is the bitter taste associated with the necessary preservatives that must be added. Liquid antacid preparations are generally susceptible to microbial contamination; Ref. "Microbiological Stability of Oral Dosage Forms, Problems with Liquid Antacids", S.T.P. Pharma 1 (8) 720-726 (1985). The pH of any aqueous based solution is critical to controlling the microbial growth within the solution. Generally, acidic solutions (less than pH 4.5) or alkaline solutions (above pH 9.5) are less susceptible to microbial growth than neutral solutions (pH 6-9); Ref. "Preservative-Free and Self-Preserving Cosmetics and Drugs", Ed. J. J. Kabara and D. S. Orth, pg.245-246 (1996). Under most circumstances, the ability to restrict this microbial growth can be aided by the addition of a preservative. The degradation of the preservative in solution can in turn be affected by the pH of the finished product. In most situations, there is a perfect match between the finished product's pH and the pH range at which the preservative is most efficacious.
Calcium carbonate in suspension typically has a pH value in the slightly alkaline range of 8.5-9.0; Ref. Ullmann's Encyclopedia of Industrial Chemistry, 5th Edition, Vol. A15, pg. 320. No preservative systems approved in the United States function optimally at this pH. The alkyl esters of parahydroxybenzoic acid (the parabens, e.g. butylparaben, methylparaben and propylparaben) are most widely used as preservatives because they offer the most efficacious option, but they degrade over time and this degradation process increases exponentially with an increase in pH; Ref. "A Comparative Study of the Effectiveness of Preservatives in Twelve Antacid Suspensions" Drug Development and Industrial Pharmacy 13(8), 1429-1446 (1987). Consequently, in order to achieve adequate preservative levels throughout the shelf life of a product with an alkaline pH, higher levels of the preservative must be added initially. This can affect the taste of the finished product however, because preservatives such as the parabens are known to have a poor taste.
Accordingly, there is a need for a preservative system for liquid antacid preparations having pH levels above 7 which effectively inhibits microbial contamination over the shelf life of the product without adversely affecting the taste of the finished product.
One way to inhibit degradation of the preservative would be to lower the pH of the antacid suspension. This may be done through the addition of buffers such as citric acid and tartaric acid. For example, U.S. Pat. No. 5,455,050 discloses calcium carbonate/magnesium salt antacid suspensions containing a carboxylic acid buffering agent such as tartaric acid. However, in order to lower the pH sufficiently to a level of around pH 7 where preservative degradation is minimal, large amounts of these buffers are required. The addition of such amounts of these acidic buffers can in turn adversely affect the acid neutralizing capacity of the antacid. U.S. Pat. No. 5,498,426 pertains to stabilizing the pH of a calcium carbonate suspension in the pH range of 7.5-8.5. It should be noted that these preparations still contain parabens which result in a poor tasting product and sub-optimal patient compliance. Thus, there is a need for a method of preserving calcium carbonate antacid liquid suspensions that would also result in a pleasant tasting product.